New biochemistry in the Rhodanese-phosphatase superfamily: emerging roles in diverse metabolic processes, nucleic acid modifications, and biological conflicts

Abstract

The protein-tyrosine/dual-specificity phosphatases and rhodanese domains constitute a sprawling superfamily of Rossmannoid domains that use a conserved active site with a cysteine to catalyze a range of phosphate-transfer, thiotransfer, selenotransfer and redox activities. While these enzymes have been extensively studied in the context of protein/lipid head group dephosphorylation and various thiotransfer reactions, their overall diversity and catalytic potential remain poorly understood. Using comparative genomics and sequence/structure analysis, we comprehensively investigate and develop a natural classification for this superfamily. As a result, we identified several novel clades, both those which retain the catalytic cysteine and those where a distinct active site has emerged in the same location (e.g. diphthine synthase-like methylases and RNA 2′ OH ribosyl phosphate transferases). We also present evidence that the superfamily has a wider range of catalytic capabilities than previously known, including a set of parallel activities operating on various sugar/sugar alcohol groups in the context of NAD+-derivatives and RNA termini, and potential phosphate transfer activities involving sugars and nucleotides. We show that such activities are particularly expanded in the RapZ-C-DUF488-DUF4326 clade, defined here for the first time. Some enzymes from this clade are predicted to catalyze novel DNA-end processing activities as part of nucleic-acid-modifying systems that are likely to function in biological conflicts between viruses and their hosts.

A Rhodanese‐Like Enzyme that Catalyzes Desulfination of Ergothioneine Sulfinic Acid

“…Rhodanese‐like ETSDs assume the same function as the previously reported metal‐dependent ETSDs, [6] suggesting that the two enzyme types emerged by convergent evolution. Our discovery that rhodanese‐like ETSDs can catalyze desulfination of an aromatic sulfinic acid adds a new entry to the short list of elementary reactions known to be catalyzed by members of the rhodanese‐like protein superfamily [15] . We anticipate that this finding will help with the functional characterization of putative rhodanese‐like enzymes in general, and more specifically with the identification of catabolic pathways of sulfur‐containing natural products.…”

“…The unusual active site motif in rhodanese‐like ETSDs may be related to their unusual activity. Catalytic desulfination is unprecedented for rhodanese‐like enzymes which usually catalyze either sulfur‐, selenium‐ or phosphate transfer or arsenate reduction [15] . There are only four other enzyme types known to catalyzed elimination of SO 2 from a carbon scaffold: 2′‐hydroxybiphenyl‐2‐sulfinate desulfinase (EC 3.13.1.3), [16] 3‐sulfinopropanoyl‐CoA desulfinase (EC 3.13.1.4), [17] aspartate β‐decarboxylases which catalyze SO 2 elimination from cysteine sulfinic acid as a side activity, [18] and metal‐dependent ETSDs.…”